Tolerability and preliminary activity of the potent, selective, oral CDK7 inhibitor SY-5609 in combination with fulvestrant in patients with advanced hormone receptor-positive (HR+), HER2- breast cancer (BC).
Authors: Dejan Juric, Debra L. Richardson, Babar Bashir, Manish Sharma, Kyriakos P. Papadopoulos, Sara Mathews, Graeme Hodgson, Susan Henry, Sofia Paul, Terence Hall, David A. Roth, Michael Kelly, Tanya Abdul Malak, Virginia Klimek
Journal: Journal of Clinical Oncology (2023)

3081 Background: SY-5609 is an oral, reversible, potent, and selective inhibitor of CDK7, a key regulator of transcription and cell cycle, currently under investigation in a Phase 1 study in patients (pts) with select advanced solid tumors (NCT04247126). Single agent (SA) dose escalation is ongoing, using a 7 days on/7 days off (7/7) dosing schedule that optimized tolerability (Sharma 2021) and showed a correlation of antitumor activity with higher exposures. SY-5609 may address multiple CDK4/6 inhibitor resistance mechanisms and potentiates SERD activity in CDK4/6 inhibitor-resistant xenograft models (Johannessen 2019). In this Phase 1 study, it was combined with the SERD fulvestrant in advanced HR+, HER2- BC pts who are refractory to CDK4/6 inhibitor + hormonal therapy. Methods: Evaluation of SY-5609 + fulvestrant began with a SY-5609 dose that had cleared the SA dose-limiting toxicity (DLT) evaluation period. SY-5609 was dosed once daily at 3 mg or 4 mg on a 21 days on/7 days off (21/7), 5 days on/2 days off (5/2), or 7/7 schedule and was escalated using a 3+3 design, guided by safety and reports of Cycle 1 qualifying safety events (QSEs), which matched SA DLT criteria. Fulvestrant was dosed at the approved dose/schedule. Safety and tolerability of SY-5609 + fulvestrant and SY-5609 PK were secondary objectives. Exploratory objectives included preliminary antitumor activity (RECIST v1.1.). Results: As of 12 Oct 2022, 14 pts (median age 63; range 46 - 83) received SY-5609 at 3 mg on a 21/7 schedule (n=8) or at 4 mg on a 5/2 (n=5) or 7/7 (n=1) schedule in combination with fulvestrant. Pts had advanced disease, including 79% with liver lesions, and a median of 5.5 (range 2 - 12) prior therapies; 100% had prior hormonal therapy, including 71% who received prior fulvestrant. The majority of adverse events (AEs) were low-grade and reversible. Related AEs (≥10%) included nausea, diarrhea, fatigue, thrombocytopenia, and hot flush. Related ≥Grade 3 AEs were reported in 3 pts (21%), including 1 QSE of Grade 3 thrombocytopenia at 4 mg 5/2. The highest tolerated dose in combination with fulvestrant was not reached. Stable disease (SD) was observed in 5/12 (42%) evaluable pts. SD with tumor shrinkage and/or SD &gt;6 months was observed in 4 pts previously treated with fulvestrant and in pts with liver lesions and/or TP53 mutations. SY-5609 exposure in combination with fulvestrant appeared comparable to SA at Day 1. Conclusions: SY-5609 + fulvestrant has an acceptable safety profile consistent with SA SY-5609 or fulvestrant. The mechanistic rationale for CDK7 inhibition in HR+, HER2- BC and the tolerability and encouraging early activity in this heavily pretreated population support future investigation of SY-5609 in combination with SERDs, including defining the maximum tolerated combination dose using the 7/7 SY-5609 schedule. Clinical trial information: NCT04247126 .